Immunomodulatory, trypanocide, and antioxidant properties of essential oil fractions of Lippia alba (Verbenaceae)

Abstract

Background Parasite persistence, exacerbated and sustained immune response, and continuous oxidative stress have been described to contribute to the development of the cardiac manifestations in Chronic Chagas Disease. Nevertheless, there are no efficient therapies to resolve the Trypanosoma cruzi infection and prevent the disease progression. Interestingly, trypanocide, antioxidant, and immunodulatory properties have been reported separately for some major terpenes, as citral (neral plus geranial), limonene, and caryophyllene oxide, presents in essential oils (EO) extracted from two chemotypes (Citral and Carvone) of Lippia alba. The aim of this study was to obtain L. alba essential oil fractions enriched with the aforementioned bioactive terpenes and to evaluate the impact of these therapies on trypanocide, oxidative stress, mitochondrial bioenergetics, genotoxicity, and inflammatory markers on T. cruzi-infected macrophages. Methods T. cruzi-infected J774A.1 macrophage were treated with limonene-enriched (ACT1) and citral/caryophyllene oxide-enriched (ACT2) essential oils fractions derived from Carvone and Citral-L. alba chemotypes, respectively. Results ACT1 (IC50 = 45 ± 1.7 μg/mL) and ACT2 (IC50 = 80 ± 1.9 μg/mL) exhibit similar trypanocidal effects to Benznidazole (BZN) (IC50 = 48 ± 2.5 μg/mL), against amastigotes. Synergistic antiparasitic activity was observed when ACT1 was combined with BZN (∑FIC = 0.52 ± 0.13 μg/mL) or ACT2 (∑FIC = 0.46 ± 1.7 μg/mL). ACT1 also decreased the oxidative stress, mitochondrial metabolism, and genotoxicity of the therapies. The ACT1 + ACT2 and ACT1 + BZN experimental treatments reduced the pro-inflammatory cytokines (IFN-γ, IL-2, and TNF-α) and increased the anti-inflammatory cytokines (IL-4 and IL-10). Conclusion Due to its highly trypanocidal and immunomodulatory properties, ACT1 (whether alone or in combination with BZN or ACT2) represents a promising L. alba essential oil fraction for further studies in drug development towards the Chagas disease control.

Immunomodulation and Antioxidant Activities as Possible Trypanocidal and Cardioprotective Mechanisms of Major Terpenes from Lippia alba Essential Oils in an Experimental Model of Chronic Chagas Disease

“…These findings suggest that BNZ, even in subtherapeutical doses, causes an antagonist effect on the Th1 response triggered by LIMOX therapy. These results align with those of Quintero et al [ 9 ] who reported that therapies composed of BNZ, alone or in combination with L. alba fractions (rich in limonene and citral/caryophyllene oxide), impaired IL-4 secretion by T. cruzi -infected macrophages.…”

“…This activity was also exhibited in in vivo models applied to Wistar rats with chronic T. cruzi infection, which were treated with synergistic fractions of these EOs enriched in limonene and caryophyllene oxide [ 10 ]. Recently, in vitro immunomodulatory properties on macrophages infected with T. cruzi were also ascribed to these phytoderivatives [ 9 ].…”

“…In the same work, Quintero et al [ 9 ] showed that the synergistic combination of L. alba fractions rich in limonene and citral/caryophyllene oxide produced a significant reduction of the pro-inflammatory cytokines (IFN-γ, IL-2, and TNF-α), with a concomitant increase of the anti-inflammatory cytokines (IL-4 and IL-10), in the extracellular media of the infected macrophages [ 9 ]. Although both studies (the aforementioned as well as the current work) show evidence of an immunomodulatory effect (reduction of all pro-inflammatory cytokines with significant elevation of IL-4) by fractions derived from L. alba EOs enriched in limonene and caryophyllene oxide, a significant disagreement exists with respect to the behavior of IFN-γ [ 9 ]. In this context, the elevated IFN-γ levels observed only in the present in vivo study could be explained by additional compensatory cellular mechanisms converging in the global response of the innate immune system, which can be uniquely perceived in a context of cardiac tissue [ 25 ].…”

“…N.E. Brown essential oils (EOs) rich in terpenes such as limonene, citral, and caryophyllene oxide [ 8 , 9 ]. In addition, trypanocidal and cardioprotective qualities have also been ascribed to these oils in animals with chronic T. cruzi infection [ 10 ].…”

Chemical Composition, Antioxidant, Antibacterial, and Antibiofilm Activities of Backhousia citriodora Essential Oil

“…It has been reported that the antioxidant capacity of oxygenated compounds could be ascribed to the free electrons, due to high oxygenation [ 54 , 55 ]. The major compounds, geranial and neral, have been reported in high levels in EO of Cymbopogon citratus (lemongrass) (70% to 85%) [ 56 ] and Lippia alba (70.6% to 79.0%) [ 57 ], exhibiting strong antioxidant activity [ 58 , 59 , 60 ]. Recent studies have associated antioxidant activity to geranial and neral by demonstrating that these compounds are active in scavenging ROS [ 61 , 62 , 63 ].…”